Oncogenic Gene Regulatory Networks

致癌基因调控网络

• 批准号: 7539157
• 负责人: JOSEPH R NEVINS
• 金额: $ 28.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539157
• 关键词: Affect; Applications Grants; Characteristics; Computer Analysis; Conflict (Psychology); Dependency; Development; Event; Funding; Gene Activation; Gene Expression; Gene Expression Profile; Gene Order; Genes; Genome; Goals; Grant; Human; Human Development; Malignant Neoplasms; Measures; Methodology; Methods; Molecular Profiling; Mutation; Nature; Oncogenic; Pathway interactions; Pattern; Process; Proteins; RNA Interference; Regulation; Regulator Genes; Regulatory Element; Research; Sampling; Sequence Analysis; Series; Signal Pathway; Signal Transduction; Small Interfering RNA; Structure; Study Section; TP53 gene; Time; Work; cell growth; computerized tools; falls; loss of function; malignant breast neoplasm; promoter

DESCRIPTION (provided by applicant): The overall goal of the work described in this proposal is to achieve a deeper and integrated understanding of the nature of oncogenic signaling pathways and networks. Studies to date have focused on the identification and characterization of immediate targets for various oncogenic regulatory activities but fall short of developing a comprehensive and integrated view of the pathways. Our recent work has developed methodologies, using genome-scale measures of gene expression, together with advanced computational tools, to develop a more detailed understanding of the gene regulatory networks associated with the action of various oncogenic activities. The importance of the work lies in the fact that this group of activities have been shown to be critical for normal cellular growth control; deregulation of activities such as Ras, Myc, and the Rb pathway are central to the development of cancer. The specific objectives of this proposal, that will aim to accomplish this overall goal, include the identification of gene regulatory networks controlled by the action of various oncogenic signaling activities through an analysis of genome-scale expression patterns. This will involve work to further explore pathways regulated by Ras, Myc, and E2Fs and then will be extended to other important pathways including Src, Abl, p53 and others. We will also apply newly developed methods for gene expression analysis that we believe will help to dissect the complexity of the signaling pathways. We will then employ these signatures of oncogenic pathways to characterize a series of human cancers for deregulation of the oncogenic signaling pathways as an approach to reconstructing the gene regulatory events associated with the development of human cancer. Additional work will aim to identify structure within the pathways, ordering genes with respect to characteristics of promoter structure suggesting common regulatory modules, as well as functional relationships between genes in the pathways. Finally, we will employ siRNA molecules as a mechanism to dissect the regulatory networks, identifying functional relationships and dependencies. Our goal is to develop a deeper understanding of these gene expression networks and importantly, given the established relationships between many of these pathways, we aim to not just define the downstream targets of these activities but to develop a comprehensive picture of the events associated with the activation of the pathway. Ultimately, this will also involve an integration of the pathways by understanding how the activation of one pathway affects another.

描述（由申请人提供）：本提案中描述的工作的总体目标是实现对致癌信号通路和网络性质的更深入和综合理解。迄今为止的研究主要集中在识别和表征各种致癌调控活动的直接靶点，但缺乏对这些途径的全面和综合的认识。我们最近的工作已经开发了方法，使用基因组规模的基因表达的措施，与先进的计算工具，以开发一个更详细的了解与各种致癌活动的行动相关的基因调控网络。这项工作的重要性在于，这组活动已被证明对正常细胞生长控制至关重要; Ras，Myc和Rb通路等活动的失调是癌症发展的核心。该提案的具体目标，旨在实现这一总体目标，包括通过分析基因组规模的表达模式，确定由各种致癌信号活动的作用控制的基因调控网络。这将涉及进一步探索由Ras，Myc和E2 Fs调节的途径，然后将扩展到其他重要途径，包括Src，Abl，p53等。我们还将应用新开发的基因表达分析方法，我们相信这将有助于剖析信号通路的复杂性。然后，我们将采用这些特征的致癌途径来表征一系列人类癌症的致癌信号通路的失调作为一种方法来重建与人类癌症的发展相关的基因调控事件。额外的工作将旨在确定结构内的途径，排序基因的启动子结构的特点，建议共同的监管模块，以及基因之间的功能关系的途径。最后，我们将采用siRNA分子作为一种机制来剖析调控网络，确定功能关系和依赖性。我们的目标是更深入地了解这些基因表达网络，重要的是，考虑到许多这些途径之间的关系，我们的目标不仅是定义这些活动的下游靶点，而且要全面了解与途径激活相关的事件。最终，这也将涉及通过了解一种途径的激活如何影响另一种途径来整合这些途径。